Abstract
BACKGROUND: Carotid plaques result from a blockage or narrowing of carotid arteries associated with severe atherosclerotic cardiovascular diseases. We aimed to assess the effect of marine n-3 fatty acid supplementation on carotid plaques among patients with diabetes and whether the effect was modified by genetics. METHODS: In this 14 month double-blind, randomized controlled trial, 415 patients with type 2 diabetes (T2D) were randomly assigned to receive high-dose (3.0 g/day) or low-dose (1.5 g/day) marine n-3 fatty acids (fish oil) or placebo (refined olive oil). The primary outcome was the prevalence of carotid plaques. Secondary outcomes included changes in NMR-derived lipoprotein subclasses. Genetic interactions with the supplementation were also explored. RESULTS: 383 participants (92.3%) completed the 14 month intervention, and 359 patients (86.5%) completed carotid ultrasound exams. Fish oil supplementation did not significantly reduce the carotid plaque prevalence (P trend = 0.111). Compared to the placebo, the odds ratios (95% CIs) of carotid plaque risk were 1.11 (0.56-2.22) and 0.54 (0.26-1.13) for low-dose and high-dose groups, respectively. Fish oil supplementation also showed no significant effect on the incidence of new carotid plaques (P for trend = 0.304) or the regression of existing plaques (P for trend = 0.390). High-dose intervention significantly reduced remnant cholesterol, LDL-1-triglycerides (TG), HDL-4-TG, and HDL-3-TG. In subgroups by genetic risk, the high-dose intervention significantly reduced carotid plaque risk specifically in patients with a low genetic risk for remnant cholesterol, with no significant benefit observed in those with medium or high genetic risk (P for interaction = 0.008; FDR = 0.056). CONCLUSION: In patients with T2D, 14 month marine n-3 fatty acid supplementation does not reduce carotid plaque risk but improves lipoprotein profile. The anti-atherosclerotic effect appeared significant in patients with a low genetic risk of remnant cholesterol, warranting further investigation into personalized nutritional strategies. TRIAL REGISTRATION: Clinicaltrials.gov NCT03708887.